Abstract The hippocampus is involved in several learning and memory tasks and patients with Fragile X syndrome (FXS) display a variety of phenotypes related to hippocampal dysfunction. Voltage-gated ion channels are critical to information processing by hippocampal circuits. H-channels (Ih) influence subthreshold synaptic inputs, while Na+ and K+ channels control the generation and propagation of dendritic spikes and action potentials. The functional expression of dendritic A-type K+ channels, IKA, is reduced in the dendrites of CA1 pyramidal neurons in the fmr1-/y mouse model of FXS. In order to understand the mechanisms by which the loss of FMRP results in the loss of dendritic IKA in FXS, we used a novel virus-based expression system to restore FMRP expression to a small population of CA1 pyramidal neurons. Dendritic IKA in FMRP-replaced CA1 neurons was higher than nearby FMRP-negative neurons. These experiments suggest that FMRP regulates IKA in a cell autonomous manner. We found that long-term potentiation of perforant path (PP) inputs from the entorhinal cortex onto the distal dendrites of CA1 neurons was absent in fmr1-/y mice. There was a significant attenuation of Ca2+ signals during PP stimulation suggesting that a loss of dendritic Ca2+ contributed the impairment of synaptic plasticity. We also found that dendritic-targeting oreins-lacunosum moleculare interneurons have altered subthreshold properties and action potential firing in fmr1-/y mice. These changes would have profound influence of the dendritic inhibition imposed by these neurons. Taken together, these data suggest that hippocampal circuit function, in particular dendritic integration of excitatory and inhibitory inputs, is impaired in FXS. We propose to investigate the cellular abnormalities and circuit dysfunction in the hippocampus in FXS. Our central hypothesis is that channelopathies alter the integrative and output ability of neurons in the CA1 region of the hippocampus, resulting in hippocampal circuit dysfunction. We will use a combination of in vitro electrophysiology and two-photon calcium imaging in conjunction with genetic, biochemical, and behavioral approaches to test this central hypothesis. The complementary specific aims will address molecular mechanisms, synaptic plasticity, and circuit dysfunction in the hippocampus of the fmr1-/y mouse model of FXS. This proposal will address important mechanistic questions about the etiology of molecular, cellular and circuit pathophysiology in the medial prefrontal cortex in FXS. Completion of this study will identify novel protein targets of FMRP with the potential for therapeutic interventions.